Cytomegalovirus (CMV) is a member of Herpesviruses, all members of which derived from a progenitor herpesvirus (HV) ~200M years ago. As obligate intracellular pathogens, the fact that HV's remain extant to infect their hosts suggests highly evolved viral mechanisms that counter host immune responses. The sophistication of viral immunomodulation is emphasized by the ability of HV's to maintain a lifelong persistence within immune competent hosts. Emerging evidence indicates that a common mechanistic link by which different CMV members attenuate the functionality of host immunity is by targeting the cellular interleukin-10 (cIL-10) signaling pathway. Only primate CMV's (HCMV and RhCMV) encode a viral version of cIL-10 (cmvIL-10 and rhcmvIL-10, respectively) that, despite extreme genetic drift from the originally transduced cIL-10 gene, has the identical immunosuppressive properties of cIL10. In parallel approaches conducted in rhesus macaques (RM) as part of our current funding, we have shown that rhcmvIL-10 is essential for (i) acute and long-term modulation of host immune responses and (ii) enabling long-term shedding of virus in bodily fluids following parenteral RhCMV challenge. Our results strongly support the notion that rhcmvIL-10 is a critical determinant of the viral proteome that skews virus-host interactions towards those that favor the establishment of a persistence in an immune competent host. We hypothesize that immunization of naive monkeys against rhcmvIL-10 alone can significantly impair the virus' ability, following mucosal RhCMV challenge, to enter into a state of persistence that is characterized by long-term viral shedding in bodily fluids. Our study will demonstrate that vaccine-mediated neutralization of rhcmvIL-10 can protect against repeated mucosal exposure of antigenic variants of RhCMV through the following Aims. (1) Immunization of RhCMV-uninfected RM with non-functional forms of rhcmvIL-10; (2) Mucosal challenge of immunized RM by introducing them into a cohort of RhCMV-excreting RM under housing conditions that enable horizontal transmission of RhCMV; (3) Development and in vitro characterization of non-functional forms of HCMV cmvIL-10; (4) Induction of neutralizing antibodies (N-Ab) against cmvIL-10 in vaccinated RM.